Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by memory loss, language deterioration, impaired visuospatial skills, poor judgment, and indifferent attitude. It is the most common form of dementia, affecting nearly 50% of the elderly population over 85 years of age. There is currently no effective treatment to prevent the disease.
One of the major histopathological hallmarks of Alzheimer's disease is senile plaques which are found only in the brain, and especially in regions associated with memory, reasoning and cognition. The major constituent of senile plaques is amyloid β protein, an insoluble 40-42 amino acid polypeptide. Amyloid β protein is normally found in the plasma and cerebrospinal fluid of healthy individuals although its function is unknown. In the disease state increased production and/or reduced removal of amyloid β protein results in increases in protein levels in plasma and cerebrospinal fluid and accumulation of the protein in the brain.
Amyloid β protein is derived from amyloid precursor protein (APP) by proteolytic cleavage. Processing of APP to amyloid β protein and other APP cleavage fragments is governed by a group of enzymes termed secretases. One type of secretase, γ-secretase, is responsible for the protein cleavage that gives rise to amyloid β protein. Although the existence of a protein having the activity of γ-secretase has been suggested, neither the gene encoding the protein, nor the protein itself has been completely isolated and characterized.
Thus, there is a continuing need in the art for compounds that can specifically inhibit proteolytic cleavage of APP, thereby inhibiting amyloid β protein production. The present invention meets this and related needs by providing a family of novel compounds and related methods of use.